The principal mediator of androgenic activity in some target organs, e.g., the prostate, is 5.alpha.-dihydrotestosterone ("DHT"), formed locally in the target organ by the action of 5.alpha.-reductase, which converts testosterone to DHT. Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system. Inhibitors of 5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. Nos. 4,377,584, issued Mar. 22, 1983, and 4,760,071, issued Jul. 26, 1988, both assigned to Merck & Co., Inc. It is now known that a second 5.alpha.-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (November 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5.alpha.-reductase 1 (or 5.alpha.-reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5.alpha.-reductase 2 (or 5.alpha.-reductase type 2).
The reduction of .DELTA.-5 steroidal alkenes to the corresponding saturated compounds is an important step in the synthesis of steroid end-products useful as 5.alpha.-reductase inhibitors.
Platinum, palladium/carbon, and noble metals such as nickel have been previously used as catalysts in the reduction of .DELTA.-5 steroidal enelactams to prefererentially yield the corresponding 5.alpha.-steroid. The degree of selectivity varies according to the particular steroidal enelactam being reduced. The best selectivity achieved using these catalysts to reduce 4,7.beta.-dimethyl-4-aza-cholest-5-ene-3-one and its 4-NH analog is about 100:1 of .alpha.:.beta. product. Because the resulting .alpha./.beta. mixture can be purified only with great difficulty, it was desirable to develop a reduction process exhibiting greater selectivity for the .alpha.-reduction product. Furthermore, none of the previously described reductions, catalytic or otherwise, offered any way to selectively direct hydrogenation to obtain the 5.beta. reduction products which are also useful as 5.alpha.-reductase inhibitors.
The instant invention provides an improved method for stereoselective reduction of certain .DELTA.-5 steroidal enelactams. In the case of 4,7.beta.-dimethyl-4-aza-cholest-5-ene-3-one, process parameters can be adjusted to preferentially yield the .alpha.-reduction product over the .beta.-reduction product in a ratio of about 500:1. The .alpha.-reduction product of 7.beta.-methyl-4-aza-cholest-5-ene-3-one is selectively formed over the .beta.-reduction product in a ratio of about 264:1. Alternatively, the process parameters can be varied to selectively yield the .beta.-reduction product of 4,7.beta.-dimethyl-4-aza-cholest-5-ene-3-one and its 4-NH analog over the .alpha.-reduction products by ratios of about 60:1 and 90:1 respectively.